Healthy Subjects (HS), Obese Adult Participants at Risk of Cardiovascular Disease
Conditions
Keywords
NLRP3 Inhibitor, ISM8969
Brief summary
This is a single center, phase 1, randomized, double-blind, placebo-controlled sequential study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of single and multiple ascending oral doses of ISM8969 in healthy adults and elderly participants and obese adult participants at risk of cardiovascular disease.
Interventions
DRUGISM8969 tablets or placebo
Administration: Oral
Sponsors
InSilico Medicine Hong Kong Limited
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
Yes
Inclusion criteria
Participants must meet all the following criteria to be included in the study: Inclusion criteria 1\~4 are only for the healthy participants in the SAD and MAD study: 1. Male or female participants, including adult participants (≥18 and \<65 years of age) for the SAD cohorts 1-6 and MAD cohorts 1-3, and elderly participants (≥65 and ≤80 years of age) for MAD cohort 4. 2. Body mass index (BMI) \>18.5 and \<30.0 kg/m2 and body weight ≥50.0 kg for males and ≥45.0 kg for females. 3. Non-smokers (no use of tobacco or nicotine products within 1 month prior to screening). 4. Healthy as defined the current protocol. Inclusion criteria 5\~9 are only for the obese participants at risk of cardiovascular disease in MAD study): 5. Male or female, ≥18 and ≤65 years of age. 6. 30.0 kg/m2 ≤ BMI \< 42.0 kg/m2. 7. No change in body weight or self-reported change of less than 5.0% within 3 months before screening. 8. Presence of 1 or more risk factors for cardiovascular disease such as hypertension, hyperlipidemia. If present, must be controlled with stable medication dose/therapy (defined as a stable medication dose/therapy for 3 months or longer). 9. hsCRP ≥3 mg/L.
Exclusion criteria
Participants for whom any of the following applies will be excluded from the study: 1. Columbia suicide severity rating scale (C-SSRS) score above Type 1 ideation. 2. Positive serology test results for hepatitis B surface antigen (HBsAg), hepatitis C virus (HCV) antibody, human immunodeficiency virus (HIV) antigen and antibody, treponema pallidum antibody or QuantiFERON®-TB test at screening. 3. Positive pregnancy test or lactating female participant. 4. History of any central nervous system (CNS) disorder or history of seizure of any cause. 5. Clinically significant 12-lead ECG, physical examination, vital signs or laboratory abnormalities at screening, including but not limited to defined in the protocol. 6. History of significant cardiovascular or cerebrovascular disease within 6 months before screening, including but not limited to defined in the protocol. 7. History of an active or untreated malignancy or are in remission from a clinically significant malignancy (other than basal- or squamous-cell skin cancer, or in situ carcinomas of the cervix) for less than 5 years; or there is a potential malignancy during screening. 8. Participation in a clinical research study involving the administration of an investigational or marketed drug or device within 30 days (or 5 half-lives, whichever is longer) prior to the first dosing, administration of a biological product in the context of a clinical research study within 90 days (or 5 half-lives, whichever is longer) prior to the first dosing, or concomitant participation in an investigational study involving no drug or device administration. 9. Presence of contraindication to lumbar puncture or lumbar catheter as judged by Investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The incidence of Adverse Events (AEs) after single or multiple doses of ISM8969 tablets. | Up to 14 days after last dose. | To evaluate the safety and tolerability of ISM8969. |
| Number of Participants with Clinical Laboratory Abnormalities, and Abnormalities in Vital Signs, Physical Examinations,12-lead ECG | Up to 14 days after last dose. | Vital signs (blood pressure, heart rate, respiratory rate, and oral temperature), physical examinations, 12-lead ECG(heart rate , PR interval, QT interval, RR interval, QTcF and QRS),and clinical laboratory tests (hematology, biochemistry, coagulation and urinalysis, etc.) |
| C-SSRS Score(Type 1 to Type 5) | Up to 14 days after last dose. | The C-SSRS(Columbia Suicidality Severity Rating Scale) is a suicidal ideation and behavior rating scale to evaluate suicide risk, higher C-SSRS scores mean a worse outcome. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximal observed plasma concentration (Cmax）. | Day 1 and Day 14 after dose. | To characterize plasma PK of ISM8969 after the first dose and at steady state. |
| Time when the maximal concentration is observed (Tmax). | Day 1 and day 14 after dose. | To characterize plasma PK of ISM8969 after the first dose and at steady state. |
| Area under the concentration-time curve from time zero to the last observed concentration (AUC0-t). | Day 3 and Day 17 after dose. | To characterize plasma PK of ISM8969 after the first dose and at steady state. |
| Area under the concentration-time curve from time zero to infinity (extrapolated)(AUC0-inf). | Day 3 and Day 17 after dose. | To characterize plasma PK of ISM8969 after single and multiple dose administration. |
| Terminal elimination half-life(T½). | Day 3 and Day 17 after dose. | To characterize plasma PK of ISM8969 after single and multiple dose administration. |
| Apparent clearance (CL/F). | Day 1 and Day 14 after dose. | To characterize plasma PK of ISM8969 after single and multiple dose administration. |
| Apparent volume of distribution (V/F). | Day 1 and day 14 after dose. | To characterize plasma PK of ISM8969 after single and multiple dose administration. |
| Maximal observed cerebrospinal fluid(CSF) concentration (Cmax,csf). | Day 14 after dose. | To characterize cerebrospinal fluid(CSF) PK of ISM8969 at steady state. |
| Minimal observed concentration at steady-state (Cmin,ss). | Day 14 before the last dose. | To characterize plasma PK of ISM8969. |
| Minimal observed cerebrospinal fluid(CSF) concentration at steady-state (Cmin,ss). | Day 14 before the last dose. | To characterize PK of ISM8969 in cerebrospinal fluid (CSF). |
| Accumulation ratio (Day 14 : Day 1) (Racc). | Day 14 after dose. | To characterize the PK of ISM8969. |
| Change from baseline in the concentration of blood high sensitivity C-reactive protein(hsCRP). | Day 14 after dose. | Concentration of hsCRP will be measured and reported. |
Countries
Australia
Contacts
CONTACTJohnny Ju
Outcome results
None listed